PPAR gamma increases HUWE1 to attenuate NF-kappa B/p65 and sickle cell disease with pulmonary hypertension

• Authors: Andrew J. Jang, Allegheny Health Network; Sarah S. Chang, Emory University; Changwon Park, Emory University; Choon Lee, Emory University; Raymond L. Benza, Allegheny Health Network; Michael J. Passineau, Allegheny Health Network; Jing Ma, Emory University; David Archer, Emory University; Roy Sutliff, Emory University; Charles Hart, Emory University; Bum-Yong Kang, Emory University
• Journal Title: Blood Advances
• Volume: Volume 5, Number 2
• Publisher: Elsevier | 2021-01-21, Pages 399-413
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1182/bloodadvances.2020002754
• Subjects: Health Sciences, Health Care Management; Health Sciences, Medicine and Surgery; Biology, Molecular; Biology, Physiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Hematology; Activated receptor gamma; Arterial hypertension; Chemical difference; Plasma endotholin-1; Chronic hypoxia; Expression; Anemia; Mice; Catheterization; Dysfunction

Abstract

Sickle cell disease (SCD)-associated pulmonary hypertension (PH) causes significant morbidity and mortality. Here, we defined the role of endothelial specific peroxisome proliferator-activated receptor g (PPARg) function and novel PPARg/HUWE1/miR-98 signaling pathways in the pathogenesis of SCD-PH. PH and right ventricular hypertrophy (RVH) were increased in chimeric Townes humanized sickle cell (SS) mice with endothelialtargeted PPARg knockout (SSePPARgKO) compared with chimeric littermate control (SSLitCon). Lung levels of PPARg, HUWE1, and miR-98 were reduced in SSePPARgKO mice compared with SSLitCon mice, whereas SSePPARgKO lungs were characterized by increased levels of p65, ET-1, and VCAM1. Collectively, these findings indicate that loss of endothelial PPARg is sufficient to increase ET-1 and VCAM1 that contribute to endothelial dysfunction and SCD-PH pathogenesis. Levels of HUWE1 and miR-98 were decreased, and p65 levels were increased in the lungs of SS mice in vivo and in hemin-treated human pulmonary artery endothelial cells (HPAECs) in vitro. Although silencing of p65 does not regulate HUWE1 levels, the loss of HUWE1 increased p65 levels in HPAECs. Overexpression of PPARg attenuated hemininduced reductions of HUWE1 and miR-98 and increases in p65 and endothelial dysfunction. Similarly, PPARg activation attenuated baseline PH and RVH and increased HUWE1 and miR-98 in SS lungs. In vitro, hemin treatment reduced PPARg, HUWE1, and miR-98 levels and increased p65 expression, HPAEC monocyte adhesion, and proliferation. These derangements were attenuated by pharmacological PPARg activation. Targeting these signaling pathways can favorably modulate a spectrum of pathobiological responses in SCD-PH pathogenesis, highlighting novel therapeutic targets in SCD pulmonary vascular dysfunction and PH.